- Email: [email protected]
Impact on Neonatal Outcome and Anthropometric Growth in Very Low Birth Weight Infants with Histological Chorioamnionitis
ORIGINAL ARTICLE
Impact on Neonatal Outcome and Anthropometric Growth in Very Low Birth Weight Infants with Histological Chorioamnionitis Shu-Chi Mu,1,2,3 Cheng-Hui Lin,1 Yi-Ling Chen,1 Hui-Ju Ma,1 Jing-Sheng Lee,1 Ming-I Lin,1 Chin-Cheng Lee,4 Tong-Jong Chen,4 Guey-Mei Jow,3 Tseng-Chen Sung1* Background/Purpose: Chorioamnionitis (CAM) is one of the main causes of preterm labor. The specific aim of our study was to evaluate neonatal outcome and anthropometric growth at the corrected age of 2 years after exposure to an adverse intrauterine event of CAM in very low birth weight (VLBW, < 1500 g) infants. Methods: One hundred and nineteen VLBW infants had adequate placental histological data available for the study. Maternal and perinatal characteristics and neonatal morbidity were determined. The infants were followed up prospectively and their anthropometric growth was recorded in the neonatal follow-up clinic for 2 years. Results: Histological CAM was evident in 64 cases (53.8%, CAM group). Patients with histological CAM delivered earlier (27.8 ± 2.9 vs. 29.6 ± 3.6 weeks, p = 0.003), and they had higher incidence of preterm premature rupture of membranes (PPROM, p < 0.001) and longer ventilation days (p = 0.001). After adjusting for gestational age, sepsis (aOR, 3.355), bronchopulmonary dysplasia (aOR, 3.018) and mechanical ventilation (aOR, 4.094) had a higher incidence in the CAM group. At the corrected ages of 6, 12, 18 and 24 months, anthropometric measurements, including body weight, body height and head circumference, were similar for the study and control infants. Conclusion: Histological CAM was associated with a higher incidence of PPROM, sepsis, bronchopulmonary dysplasia, more mechanical ventilation and longer ventilation days. However, at the age of 2 years, CAM had no impact on anthropometric growth. [J Formos Med Assoc 2008;107(4):304–310] Key Words: anthropometric growth, bronchopulmonary dysplasia, chorioamnionitis, very low birth weight
Chorioamnionitis (CAM) is one of the main causes of preterm labor and has been associated with adverse perinatal outcome in preterm infants.1 Microbial infection of the chorioamnion is detected in 60% of all preterm deliveries,2 and intrauterine infection is commonly identified in premature delivery. The rate of clinical CAM may
be higher in deliveries at earlier gestation, particularly in those patients with preterm premature rupture of membranes (PPROM). The diagnosis of histological CAM requires examination of the placenta after delivery. Higher occurrence of histological CAM in preterm placentas compared with those at term has been well documented.3,4
©2008 Elsevier & Formosan Medical Association .
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Departments of 1Pediatrics and 4Pathology, Shin Kong Wu Ho-Su Memorial Hospital, 2Institute of Clinical Medicine, National Yang-Ming University, and 3College of Medicine, Fu Jen Catholic University, Taipei, Taiwan. Received: January 24, 2007 Revised: April 14, 2007 Accepted: January 15, 2008
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*Correspondence to: Dr Tseng-Chen Sung, Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Taipei 111, Taiwan. E-mail: [email protected]
J Formos Med Assoc | 2008 • Vol 107 • No 4
Outcome and growth anthropometry in VLBW infants with chorioamnionitis
Some studies have reported an adverse effect of clinical and histopathological CAM on neonatal outcome. In full-term neonates, there were higher rates of perinatal death and neonatal sepsis in the first 48 hours of life in infants whose delivery was complicated by histopathological CAM,5,6 and neonatal morbidity was higher in this group too.7 The impaired fetal angiogenesis in the placenta might be one of the pathogenic mechanisms that contributes to increased morbidity and mortality of fetuses and newborns who are exposed to CAM and funisitis.8 The effects of CAM were neonatal sepsis in full-term babies and PPROM in preterm infants. No previous studies have investigated the effect of CAM on the growth of very low birth weight (VLBW) infants. The specific aims of our study were to evaluate neonatal outcome and anthropometric growth at the corrected age of 2 years after exposure to an adverse intrauterine environment in VLBW infants.
Methods This was a descriptive, double-cohort study of a group of VLBW neonates delivered at Shin-Kong Wu Ho-Su Memorial Hospital between January 2000 and December 2004. They were admitted to the special care nursery with the primary reason of PPROM or prematurity. After discharge, they were followed up longitudinally in the high-risk newborn follow-up clinic. All infants were free of major congenital anomalies. Gestational age was determined by menstrual history, antenatal ultrasound, and Ballard assessment.9 Neonatal characteristics and morbidities were recorded. The chronological ages were adjusted. Maternal charts were reviewed, including maternal age, delivery mode, multiple pregnancies, and use of antibiotics or steroids and assisted reproductive technology. PPROM was defined as spontaneous rupture of membranes before the onset of labor. Antepartum use of antibiotics consisted of intravenous or oral antibiotics administered within 24 hours of delivery. Antenatal steroid use consisted J Formos Med Assoc | 2008 • Vol 107 • No 4
of two doses of 12 mg betamethasone 24 hours apart. Respiratory distress syndrome (RDS) was defined as a combination of three of the following: clinical signs, oxygen requirement > 30% from 12 to 72 hours, need for assisted ventilation (continuous positive airway pressure or mechanical ventilation), and typical chest X-ray appearance. Intraventricular hemorrhage (IVH) was graded according to the Papile classification.10 Necrotizing enterocolitis (NEC) was classified as the presence of intramural gas on X-ray, perforation or evidence of intestinal necrosis at surgery or autopsy. Patent ductus arteriosus (PDA) was diagnosed by clinical signs and/or echocardiography confirmation. Sepsis was defined as a positive blood culture. Early neonatal septicemia was defined as a positive blood culture in the first 72 hours. Placental specimens included a minimum of two segments of umbilical cord, one parenchyma section including chorion and amnion, and a membrane roll that extended from the area of rupture to the margin of the placenta. Tissue sections were stained with hematoxylin and eosin. Histological CAM was defined if the chorion and amnion were infiltrated with inflammatory cells and the chorionic plate was cloudy or opaque. Clinical CAM was defined by criteria introduced by Gibbs et al.11 These criteria included a maternal temperature of 38°C or higher and two of the following: maternal heart rate > 20 bpm, fetal heart rate > 160 bpm, foul smelling amniotic fluid, fundal tenderness, and maternal white blood cell count > 14,000/mL. For survivors between 6 and 24 months of corrected age, the anthropometric growth, including weight, height and head circumference were recorded. For continuous variables, values are expressed as mean ± standard deviation unless indicated otherwise, and an independent t test was used for statistical analysis. For the categorical variables, Pearson’s χ2 test was used to compare proportions of the groups. All risk factors were proceeded by adjusted logistic regression analysis, which was performed to account for the potential confounding 305
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Table 1. Antenatal demographics*
Maternal age (yr) Gravidity Parity Cesarean delivery Twins Use of maternal steroids Use of tocolytic agents Assisted reproductive technology
CAM (n = 64)
Non-CAM (n = 55)
p
29.4 ± 5.2 2.7 ± 1.7 1.8 ± 0.9 29 (45.3) 3 (4.7) 33 (51.6) 20 (31.3) 5 (7.8)
31.2 ± 5.8 3.1 ± 2.1 1.8 ± 0.9 37 (67.3) 12 (21.8) 20 (36.4) 17 (30.9) 5 (9.1)
0.092 0.312 0.689 0.216 0.005† 0.409 0.668 0.737
*Data presented as mean ± standard deviation or n (%); †significant at p < 0.05 level. CAM = preterm infants with histological chorioamnionitis; Non-CAM = preterm infants without histological chorioamnionitis.
40 30
26
25
One hundred and nineteen cases had available placental histological data. Histological CAM was evident in 64 (53.8%) cases. Maternal characteristics are presented in Table 1. Between cases with and without histological CAM, there was a significant difference in the frequency of twin pregnancy (3/64, 4.7% vs. 12/55, 21.8%; p = 0.005), but no difference in maternal age, gravity, parity, delivery mode, use of steroid or tocolytic agent, and whether or not conception was through assisted reproductive technology. The number of cases with CAM increased with decreasing gestational age (Figure). The peak prevalence of CAM was displayed at the gestational age of 27–30 weeks (up to 48%). There was one case with clinical CAM in the histological CAM group and no cases with microbial evidence in either group. As shown in Table 2, mothers with histological CAM delivered earlier (27.8 ± 2.9 vs. 29.6 ± 3.6 weeks; p = 0.003) and had higher incidence of PPROM (30/64, 46.9% vs. 6/55, 10.9%; p < 0.001). The probability of being small for gestational age 306
26 22
22
19
20
17
16
15 10
7.6 3.7
5
Results
37
CAM Non-CAM
35 Percentage
variables of complications in premature neonates. A value of p < 0.05 was considered significant. Analyses were performed using the SPSS statistical package (SPSS Inc., Chicago, IL, USA). The study was approved by the Shin Kong Wu Ho-Su Memorial Hospital’s institutional review board.
0
3.7
0
<23
23–24 25–26 27–28 29–30 Gestational age
>30
Figure. Distribution of cases with histological chorioamnionitis (CAM) and non-CAM based on gestational age (weeks).
(SGA) was lower in infants with CAM (SGA, 19/64, 29.7% vs. 30/55, 54.5%; p = 0.005). There were no significant differences in birth weight, Apgar scores at 1 and 5 minutes, gender, duration of PPROM (hours) and meconium staining. Neonatal outcomes are shown in Table 3. In the CAM group, surfactant use (48/64, 75.0% vs. 30/55, 54.5%; p = 0.022), sepsis (21/64, 32.8% vs. 7/55, 12.7%; p = 0.016) and bronchopulmonary dysplasia (BPD; 25/64, 39.1% vs. 10/55, 18.2%; p = 0.016) were greater and the median days of ventilation (22.0 ± 28.2 vs. 7.8 ± 13.1 days; p = 0.001) were longer. The gestational ages in the two groups were different, and this may have interfered with the analysis of neonatal outcome. After adjusting for gestational age, CAM increased the risk of sepsis (aOR, 3.355; 95% CI, 1.275, 8.827), BPD (aOR, 3.018; 95% CI, 1.235, 7.378) and use of J Formos Med Assoc | 2008 • Vol 107 • No 4
Outcome and growth anthropometry in VLBW infants with chorioamnionitis
Table 2. Perinatal demographic characteristics*
Gestational age (wk) Birth body weight (g) Apgar score (1 min) Apgar score ≤ 3 (1 min) Apgar score (5 min) Apgar score ≤ 5 (5 min) Male Small for gestational age Meconium staining PPROM Duration of PPROM (hr)
CAM (n = 64)
Non-CAM (n = 55)
p
27.8 ± 2.9 1078.4 ± 274.7 4.6 ± 1.8 13 (20.3) 6.6 ± 1.6 6 (9.4) 36 (56.3) 19 (29.7) 3 (4.7) 30 (46.9) 128.3 ± 113.0
29.6 ± 3.6 1142.2 ± 274.7 5.1 ± 1.9 8 (14.5) 6.9 ± 1.6 5 (9.1) 28 (50.9) 30 (54.5) 1 (1.8) 6 (10.9) 113.8 ± 71.5
0.003† 0.211 0.154 0.478 0.259 1.000 0.576 0.005‡ 0.623 < 0.001‡ 0.768
*Data presented as mean ± standard deviation or n (%); †p < 0.05, independent t test; ‡p < 0.05, Pearson’s χ2 test. PPROM = preterm premature rupture of membranes.
Table 3. Neonatal outcomes*
Survival Mechanical ventilation Use of surfactant Sepsis with VAP Respiratory distress syndrome Bronchopulmonary dysplasia Patent ductus arteriosus IVH IVH, grades III and IV ROP, all grades ROP, ≥ stage III Necrotizing enterocolitis Ventilation duration (d) Length of hospital stay (d)
CAM (n = 64)
Non-CAM (n = 55)
p†
aOR (95% CI)
51 (79.7) 56 (87.5) 48 (75.0) 21 (32.8) 56 (87.5) 25 (39.1) 11 (17.2) 15 (23.4) 11 (17.2) 32 (50.0) 11 (17.2) 3 (4.7) 22.0 ± 28.2 63.6 ± 40.1
44 (80.0) 40 (72.7) 30 (54.5) 7 (12.7) 40 (72.7) 10 (18.2) 5 (9.1) 11 (20.0) 9 (16.4) 25 (45.5) 8 (14.5) 0 (0) 7.8 ± 13.1 78.2 ± 71.8
1.000 0.061 0.022‡ 0.016‡ 0.061 0.016‡ 0.281 0.824 1.000 1.000 1.000 – 0.001‡ 0.672
0.295 (0.089, 0.983) 4.092 (1.374, 12.187)‡ 1.841 (0.765, 4.427) 3.355 (1.275, 8.827)‡ 2.068 (0.768, 5.573) 3.018 (1.235, 7.378)‡ 1.653 (0.510, 5.359) 0.681 (0.250, 1.855) 0.536 (0.179, 1.606) 1.531 (0.709, 3.307) 1.330 (0.463, 3.820) – – –
*Data presented as n (%) or mean ± standard deviation; †p obtained from independent t test or Pearson’s χ2 test; ‡significant at p < 0.05 level. aOR = adjusted odds ratio, all adjusted for gestational age in weeks; CI = confidence interval; VAP = ventilator-associated pneumonia; IVH = intraventricular hemorrhage; ROP = retinopathy of prematurity.
mechanical ventilation (aOR, 4.092; 95% CI, 1.374, 12.187), as well as ventilation over 5 days (aOR, 2.654; 95% CI, 1.127, 6.252). The incidence of NEC was low, with three cases in the CAM group and none in the non-CAM group. There were no cases of early neonatal sepsis in either group; all 28 cases with neonatal septicemia had ventilator-associated pneumonia (VAP), and none of them had primary neonatal septicemia. Neonatal septicemia and VAP were strongly related J Formos Med Assoc | 2008 • Vol 107 • No 4
to histological CAM (21 in the CAM group and 7 in the non-CAM group). The majority of organisms included Candida parapsilosis (n = 4), Acinobacter baumannii (n = 4), Klebsiella pneumoniae (n = 3), Serratia marcescens (n = 3) and Staphylococcus epidermidis (n = 3). At the corrected ages of 6, 12, 18 and 24 months, anthropometric growth of infants, including body weight, body height and head circumference, were similar in both groups (Table 4). 307
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Table 4. Growth of anthropometry* CAM (n = 64)
Non-CAM (n = 55)
p
6 mo BW BH HC
6.8 ± 1.1 64.2 ± 3.7 50.3 ± 56.3
7.1 ± 1.0 64.8 ± 3.6 42.4 ± 1.3
0.254 0.453 0.375
12 mo BW BH HC
8.7 ± 1.2 72.8 ± 3.5 44.6 ± 1.6
8.7 ± 1.0 71.2 ± 9.3 45.0 ± 1.3
0.921 0.314 0.181
18 mo BW BH HC
10.1 ± 1.4 79.6 ± 4.1 45.9 ± 1.7
9.8 ± 1.2 78.4 ± 3.2 46.2 ± 1.4
0.284 0.153 0.442
24 mo BW BH HC
11.5 ± 2.4 85.1 ± 4.1 46.9 ± 1.7
11.2 ± 1.3 84.3 ± 3.4 46.8 ± 1.1
0.444 0.401 0.940
*Data presented as mean ± standard deviation. BW = body weight; BH = body height; HC = head circumference.
Discussion In our study, there were 53.8% of placentas with CAM, similar to Dexter et al’s report (57%).12 The number of cases of CAM increased with decreasing gestational age, which was consistent with previous studies.13 Thus, placental inflammation is a common finding in preterm gestation. The etiology of preterm delivery of a fetus with CAM might be directly related to infection; however, clinical evidence of infection is rarely detected, so the diagnosis is usually made through histologic examination of the placenta. In our study, CAM was not an indication for cesarean section, but rather, acute perinatal events were. This reflects that histological CAM is a chronic or subacute inflammatory condition of the placenta. Romero et al6 have shown that a fetal inflammatory process may be followed by the spontaneous onset of preterm labor. It is also possible that inflammation impairs placental function. The rate of maternal steroid use was 51.6% in the CAM group compared to 36.4% in the non-CAM group. In the non-CAM group, there 308
were more preterm deliveries for maternal reasons or the time from arrival to delivery was insufficient to obtain a fetal steroid response. These factors possibly accounted for differences in steroid use. In this study, there was one case of clinical CAM in the histological CAM group and no cases with microbial evidence in either group. We did not have enough cases of clinical CAM to investigate the histological findings and outcome. The prevalence of PPROM was 46.9% and 10.9% (p < 0.001) in the CAM and non-CAM groups, respectively. The cases with CAM had a longer duration of ruptured membranes.14,15 This supports the concept that intra-amniotic infection is frequently caused by organisms in the lower genital tract that ascend into the uterine cavity. In addition to preterm delivery, CAM increases neonatal morbidity and mortality. Hagberg et al16 have summarized the sequelae of CAM in both term and preterm infants. We identified a higher incidence of BPD, greater use of surfactant, and more days of ventilation in the CAM group. CAM leads to a fetal inflammatory response, which is characterized by elevated cytokine levels. CAM is J Formos Med Assoc | 2008 • Vol 107 • No 4
Outcome and growth anthropometry in VLBW infants with chorioamnionitis
reported to cause accelerated but abnormal lung maturation, which results in decreased incidence of RDS, but increased BPD.17 Our study, which showed that histological CAM increased the risk of BPD (p = 0.016; aOR, 3.018), was consistent with previous studies.17,18 However, there was no significant association between CAM and RDS (p = 0.061; aOR, 2.068). Pulmonary inflammation is a key feature in the pathogenesis of BPD. This inflammatory process, induced by multiple risk factors, is characterized by the presence of inflammatory cells, cytokines and an arsenal of additional humoral mediators in the airways and pulmonary tissue. Intrauterine exposure to proinflammatory cytokines or antenatal infection may prime the fetal lung such that minimally injurious postnatal events provoke an excessive pulmonary inflammatory response that affects normal alveolization and pulmonary vascular development. This leads to difficulty in respiratory care after birth. However, in Mehta et al’s study, CAM was not a significant risk factor for BPD among neonates born at around 34 weeks of gestation.19 A few studies have demonstrated a reduction in the incidence of RDS in neonates with histological CAM.18,20 Shimoya et al identified elevated levels of interleukin-6 in cord sera of babies with CAM.21 Interleukin promotes fetal lung maturation by inducing surfactant protein-A synthesis, thereby, reducing the incidence of RDS. Our findings differ from these studies; after adjusting for gestational age, CAM had no impact on RDS. Histological CAM was strongly associated with neonatal septicemia. Most septicemic patients were delivered within 24 hours of membrane rupture, which highlighted the potential role of infection in premature delivery. In this study, there was no case of early neonatal sepsis. These findings are not consistent with those of other studies.22,23 All the neonatal septicemia in our study occurred after the age of 3 days. Most of the organisms included C. parapsilosis, A. baumanni, K. pneumoniae and S. marcescens. They were also found in sputum culture that was aspirated from an endotracheal tube; therefore, these cases had VAP too. VAP is an airway infection J Formos Med Assoc | 2008 • Vol 107 • No 4
that develops 48 hours after the patient is intubated. Because the CAM group had longer ventilation days (p = 0.001), it was reasonable that VAP occurred more frequently in this group. In our study, CAM was a risk factor for neonatal septicemia with VAP (aOR, 3.355; 95% CI, 1.374, 12.187). There were no significant differences in PDA, retinopathy of prematurity (all grades and grade > III), IVH (all grades or stratification of grades III and IV) and NEC. This was not the same as the study of Salafia et al,24 who found that early germinal matrix/IVH occurred more frequently in infants delivered with a placenta showing amniotic inflammation. In our study, the gestational age of the CAM group was significantly shorter than that of the non-CAM group. However, the IVH incidences were similar, although theoretically, IVH occurred more frequently in babies of younger gestational age. For NEC, there were only three cases in the CAM group and none in the nonCAM group, so a type 2 error must be considered. There have been no previous studies investigating the effect of CAM on anthropometric growth. Morbidity was increased among preterm infants with CAM, thus the anthropometric growth might be affected. In our study, at corrected ages of 6, 12, 18 and 24 months, the two groups of premature infants showed similar growth, including body weight, height and head girth. In conclusion, histological CAM was associated with increased risk of BPD and sepsis in VLBW premature infants. However, it was not associated with survival, PDA, IVH, NEC, retinopathy of prematurity and anthropometric growth within 2 years after birth.
Acknowledgments This study was supervised by the Ethics Committee and Institutional Review Board of Shin-Kong Medical Center. We thank Miss Chang Chia-Han for manuscript preparation and computational analyses, Ms Li Yu-Ling for technical assistance, and Dr Bai Chyi-Huey for statistical analysis. This 309
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project was supported by a grant from Shin-Kong Wu Ho-Su Memorial Hospital (SKH-FJU-96-20).
References 1. Lahra MM, Jeffery HE. A fetal response to chorioamnionitis is associated with early survival after preterm birth. Am J Obstet Gynecol 2004;190:147–51. 2. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342:1500–7. 3. Hillier SL, Martius J, Krohn M, et al. A case-control study of chorioamnionic infection and histologic CAM in prematurity. N Engl J Med 1988;319:972–8. 4. Mueller-Heubach E, Rubinstein DN, Schwarz SS. Histologic CAM and preterm delivery in different patient populations. Obstet Gynecol 1990;75:622–6. 5. Russell P. Inflammatory lesions of the human placenta: clinical significance of acute CAM. Am J Diagn Gynecol Obstet 1979;1:127–37. 6. Romero R, Gomez R, Ghezzi F, et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998;179:186–93. 7. Zhang J, Kraus FT, Aquino TI. CAM: a comparative histologic, bacteriologic, and clinical study. Int J Gynecol Pathol 1985;4:1–10. 8. Kramer BW, Kaemmerer U, Kapp M, et al. Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth. Pediatr Res 2005;58:607–12. 9. Ballard JL, Khoury JC, Wedig K, et al. New Ballard score, expanded to include extremely premature infants. J Pediatr 1991;119:417–23. 10. Papile LA, Burnstein J, Burnstein R, et al. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants less than 1500 grams. J Peds 1978; 92:529–34. 11. Gibbs RS, Blanco JD, St Clair PJ, et al. Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis 1982;145:1–8.
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12. Dexter SC, Malee MP, Pinar H, et al. Influence of CAM on developmental outcome in very low birth weight infants. Obstet Gynecol 1999;94:267–73. 13. Polam S, Koons A, Anwar M, et al. Effect of chorioamnionitis on neurodevelopmental outcome in preterm infants. Arch Pediatr Adol Med 2005;159:1032–5. 14. Soper DE, Mayhall CG, Dalton HP. Risk factors for intraamniotic infection: a prospective epidemiologic study. Am J Obstet Gynecol 1989;161:592–6. 15. Dinsmoor MJ, Gibbs RS. Previous intraamniotic infection as a risk factor for subsequent peripartal uterine infections. Obstet Gynecol 1989;74:299–301. 16. Hagberg H, Wennerholm UB, Savman K. Sequelae of chorioamnionitis. Curr Opin Infect Dis 2002;15:301–6. 17. Jobe AH. Antenatal factors and the development of bronchopulmonary dysplasia. Semin Neonatol 2003;8:9–17. 18. Watterberg KL, Demers LM, Scott SM, et al. Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996; 97:210–5. 19. Mehta R, Nanjundaswamy S, Shen-Schwarz S, et al. Neonatal morbidity and placental pathology. Indian J Pediatr 2006;73:25–8. 20. Fung G, Bawden K, Chow P, et al. Chorioamnionitis and outcome in extremely preterm infants. Ann Acad Med Singapore 2003;32:305–10. 21. Shimoya K, Taniguchi T, Matsuzaki N, et al. Chorioamnionitis decreased incidence of respiratory distress syndrome by elevating fetal interleukin-6 serum concentration. Hum Reprod 2000;15:2234–40. 22. Yancey MK, Duff P, Kubilis P, et al. Risk factors for neonatal sepsis. Obstet Gynecol 1996;87:188–94. 23. de Araujo MC, Schultz R, Vaz FA, et al. A case-control study of histological chorioamnionitis and neonatal infection. Early Hum Dev 1994;40:51–8. 24. Salafia CM, Minior VK, Rosenkrantz TS, et al. Maternal, placental, and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks’ gestation. Am J Perinatol 1995;12:429–36.
J Formos Med Assoc | 2008 • Vol 107 • No 4
Impact on Neonatal Outcome and Anthropometric Growth in Very Low Birth Weight Infants with Histological Chorioamnionitis Shu-Chi Mu,1,2,3 Cheng-Hui Lin,1 Yi-Ling Chen,1 Hui-Ju Ma,1 Jing-Sheng Lee,1 Ming-I Lin,1 Chin-Cheng Lee,4 Tong-Jong Chen,4 Guey-Mei Jow,3 Tseng-Chen Sung1* Background/Purpose: Chorioamnionitis (CAM) is one of the main causes of preterm labor. The specific aim of our study was to evaluate neonatal outcome and anthropometric growth at the corrected age of 2 years after exposure to an adverse intrauterine event of CAM in very low birth weight (VLBW, < 1500 g) infants. Methods: One hundred and nineteen VLBW infants had adequate placental histological data available for the study. Maternal and perinatal characteristics and neonatal morbidity were determined. The infants were followed up prospectively and their anthropometric growth was recorded in the neonatal follow-up clinic for 2 years. Results: Histological CAM was evident in 64 cases (53.8%, CAM group). Patients with histological CAM delivered earlier (27.8 ± 2.9 vs. 29.6 ± 3.6 weeks, p = 0.003), and they had higher incidence of preterm premature rupture of membranes (PPROM, p < 0.001) and longer ventilation days (p = 0.001). After adjusting for gestational age, sepsis (aOR, 3.355), bronchopulmonary dysplasia (aOR, 3.018) and mechanical ventilation (aOR, 4.094) had a higher incidence in the CAM group. At the corrected ages of 6, 12, 18 and 24 months, anthropometric measurements, including body weight, body height and head circumference, were similar for the study and control infants. Conclusion: Histological CAM was associated with a higher incidence of PPROM, sepsis, bronchopulmonary dysplasia, more mechanical ventilation and longer ventilation days. However, at the age of 2 years, CAM had no impact on anthropometric growth. [J Formos Med Assoc 2008;107(4):304–310] Key Words: anthropometric growth, bronchopulmonary dysplasia, chorioamnionitis, very low birth weight
Chorioamnionitis (CAM) is one of the main causes of preterm labor and has been associated with adverse perinatal outcome in preterm infants.1 Microbial infection of the chorioamnion is detected in 60% of all preterm deliveries,2 and intrauterine infection is commonly identified in premature delivery. The rate of clinical CAM may
be higher in deliveries at earlier gestation, particularly in those patients with preterm premature rupture of membranes (PPROM). The diagnosis of histological CAM requires examination of the placenta after delivery. Higher occurrence of histological CAM in preterm placentas compared with those at term has been well documented.3,4
©2008 Elsevier & Formosan Medical Association .
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Departments of 1Pediatrics and 4Pathology, Shin Kong Wu Ho-Su Memorial Hospital, 2Institute of Clinical Medicine, National Yang-Ming University, and 3College of Medicine, Fu Jen Catholic University, Taipei, Taiwan. Received: January 24, 2007 Revised: April 14, 2007 Accepted: January 15, 2008
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*Correspondence to: Dr Tseng-Chen Sung, Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, Taipei 111, Taiwan. E-mail: [email protected]
J Formos Med Assoc | 2008 • Vol 107 • No 4
Outcome and growth anthropometry in VLBW infants with chorioamnionitis
Some studies have reported an adverse effect of clinical and histopathological CAM on neonatal outcome. In full-term neonates, there were higher rates of perinatal death and neonatal sepsis in the first 48 hours of life in infants whose delivery was complicated by histopathological CAM,5,6 and neonatal morbidity was higher in this group too.7 The impaired fetal angiogenesis in the placenta might be one of the pathogenic mechanisms that contributes to increased morbidity and mortality of fetuses and newborns who are exposed to CAM and funisitis.8 The effects of CAM were neonatal sepsis in full-term babies and PPROM in preterm infants. No previous studies have investigated the effect of CAM on the growth of very low birth weight (VLBW) infants. The specific aims of our study were to evaluate neonatal outcome and anthropometric growth at the corrected age of 2 years after exposure to an adverse intrauterine environment in VLBW infants.
Methods This was a descriptive, double-cohort study of a group of VLBW neonates delivered at Shin-Kong Wu Ho-Su Memorial Hospital between January 2000 and December 2004. They were admitted to the special care nursery with the primary reason of PPROM or prematurity. After discharge, they were followed up longitudinally in the high-risk newborn follow-up clinic. All infants were free of major congenital anomalies. Gestational age was determined by menstrual history, antenatal ultrasound, and Ballard assessment.9 Neonatal characteristics and morbidities were recorded. The chronological ages were adjusted. Maternal charts were reviewed, including maternal age, delivery mode, multiple pregnancies, and use of antibiotics or steroids and assisted reproductive technology. PPROM was defined as spontaneous rupture of membranes before the onset of labor. Antepartum use of antibiotics consisted of intravenous or oral antibiotics administered within 24 hours of delivery. Antenatal steroid use consisted J Formos Med Assoc | 2008 • Vol 107 • No 4
of two doses of 12 mg betamethasone 24 hours apart. Respiratory distress syndrome (RDS) was defined as a combination of three of the following: clinical signs, oxygen requirement > 30% from 12 to 72 hours, need for assisted ventilation (continuous positive airway pressure or mechanical ventilation), and typical chest X-ray appearance. Intraventricular hemorrhage (IVH) was graded according to the Papile classification.10 Necrotizing enterocolitis (NEC) was classified as the presence of intramural gas on X-ray, perforation or evidence of intestinal necrosis at surgery or autopsy. Patent ductus arteriosus (PDA) was diagnosed by clinical signs and/or echocardiography confirmation. Sepsis was defined as a positive blood culture. Early neonatal septicemia was defined as a positive blood culture in the first 72 hours. Placental specimens included a minimum of two segments of umbilical cord, one parenchyma section including chorion and amnion, and a membrane roll that extended from the area of rupture to the margin of the placenta. Tissue sections were stained with hematoxylin and eosin. Histological CAM was defined if the chorion and amnion were infiltrated with inflammatory cells and the chorionic plate was cloudy or opaque. Clinical CAM was defined by criteria introduced by Gibbs et al.11 These criteria included a maternal temperature of 38°C or higher and two of the following: maternal heart rate > 20 bpm, fetal heart rate > 160 bpm, foul smelling amniotic fluid, fundal tenderness, and maternal white blood cell count > 14,000/mL. For survivors between 6 and 24 months of corrected age, the anthropometric growth, including weight, height and head circumference were recorded. For continuous variables, values are expressed as mean ± standard deviation unless indicated otherwise, and an independent t test was used for statistical analysis. For the categorical variables, Pearson’s χ2 test was used to compare proportions of the groups. All risk factors were proceeded by adjusted logistic regression analysis, which was performed to account for the potential confounding 305
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Table 1. Antenatal demographics*
Maternal age (yr) Gravidity Parity Cesarean delivery Twins Use of maternal steroids Use of tocolytic agents Assisted reproductive technology
CAM (n = 64)
Non-CAM (n = 55)
p
29.4 ± 5.2 2.7 ± 1.7 1.8 ± 0.9 29 (45.3) 3 (4.7) 33 (51.6) 20 (31.3) 5 (7.8)
31.2 ± 5.8 3.1 ± 2.1 1.8 ± 0.9 37 (67.3) 12 (21.8) 20 (36.4) 17 (30.9) 5 (9.1)
0.092 0.312 0.689 0.216 0.005† 0.409 0.668 0.737
*Data presented as mean ± standard deviation or n (%); †significant at p < 0.05 level. CAM = preterm infants with histological chorioamnionitis; Non-CAM = preterm infants without histological chorioamnionitis.
40 30
26
25
One hundred and nineteen cases had available placental histological data. Histological CAM was evident in 64 (53.8%) cases. Maternal characteristics are presented in Table 1. Between cases with and without histological CAM, there was a significant difference in the frequency of twin pregnancy (3/64, 4.7% vs. 12/55, 21.8%; p = 0.005), but no difference in maternal age, gravity, parity, delivery mode, use of steroid or tocolytic agent, and whether or not conception was through assisted reproductive technology. The number of cases with CAM increased with decreasing gestational age (Figure). The peak prevalence of CAM was displayed at the gestational age of 27–30 weeks (up to 48%). There was one case with clinical CAM in the histological CAM group and no cases with microbial evidence in either group. As shown in Table 2, mothers with histological CAM delivered earlier (27.8 ± 2.9 vs. 29.6 ± 3.6 weeks; p = 0.003) and had higher incidence of PPROM (30/64, 46.9% vs. 6/55, 10.9%; p < 0.001). The probability of being small for gestational age 306
26 22
22
19
20
17
16
15 10
7.6 3.7
5
Results
37
CAM Non-CAM
35 Percentage
variables of complications in premature neonates. A value of p < 0.05 was considered significant. Analyses were performed using the SPSS statistical package (SPSS Inc., Chicago, IL, USA). The study was approved by the Shin Kong Wu Ho-Su Memorial Hospital’s institutional review board.
0
3.7
0
<23
23–24 25–26 27–28 29–30 Gestational age
>30
Figure. Distribution of cases with histological chorioamnionitis (CAM) and non-CAM based on gestational age (weeks).
(SGA) was lower in infants with CAM (SGA, 19/64, 29.7% vs. 30/55, 54.5%; p = 0.005). There were no significant differences in birth weight, Apgar scores at 1 and 5 minutes, gender, duration of PPROM (hours) and meconium staining. Neonatal outcomes are shown in Table 3. In the CAM group, surfactant use (48/64, 75.0% vs. 30/55, 54.5%; p = 0.022), sepsis (21/64, 32.8% vs. 7/55, 12.7%; p = 0.016) and bronchopulmonary dysplasia (BPD; 25/64, 39.1% vs. 10/55, 18.2%; p = 0.016) were greater and the median days of ventilation (22.0 ± 28.2 vs. 7.8 ± 13.1 days; p = 0.001) were longer. The gestational ages in the two groups were different, and this may have interfered with the analysis of neonatal outcome. After adjusting for gestational age, CAM increased the risk of sepsis (aOR, 3.355; 95% CI, 1.275, 8.827), BPD (aOR, 3.018; 95% CI, 1.235, 7.378) and use of J Formos Med Assoc | 2008 • Vol 107 • No 4
Outcome and growth anthropometry in VLBW infants with chorioamnionitis
Table 2. Perinatal demographic characteristics*
Gestational age (wk) Birth body weight (g) Apgar score (1 min) Apgar score ≤ 3 (1 min) Apgar score (5 min) Apgar score ≤ 5 (5 min) Male Small for gestational age Meconium staining PPROM Duration of PPROM (hr)
CAM (n = 64)
Non-CAM (n = 55)
p
27.8 ± 2.9 1078.4 ± 274.7 4.6 ± 1.8 13 (20.3) 6.6 ± 1.6 6 (9.4) 36 (56.3) 19 (29.7) 3 (4.7) 30 (46.9) 128.3 ± 113.0
29.6 ± 3.6 1142.2 ± 274.7 5.1 ± 1.9 8 (14.5) 6.9 ± 1.6 5 (9.1) 28 (50.9) 30 (54.5) 1 (1.8) 6 (10.9) 113.8 ± 71.5
0.003† 0.211 0.154 0.478 0.259 1.000 0.576 0.005‡ 0.623 < 0.001‡ 0.768
*Data presented as mean ± standard deviation or n (%); †p < 0.05, independent t test; ‡p < 0.05, Pearson’s χ2 test. PPROM = preterm premature rupture of membranes.
Table 3. Neonatal outcomes*
Survival Mechanical ventilation Use of surfactant Sepsis with VAP Respiratory distress syndrome Bronchopulmonary dysplasia Patent ductus arteriosus IVH IVH, grades III and IV ROP, all grades ROP, ≥ stage III Necrotizing enterocolitis Ventilation duration (d) Length of hospital stay (d)
CAM (n = 64)
Non-CAM (n = 55)
p†
aOR (95% CI)
51 (79.7) 56 (87.5) 48 (75.0) 21 (32.8) 56 (87.5) 25 (39.1) 11 (17.2) 15 (23.4) 11 (17.2) 32 (50.0) 11 (17.2) 3 (4.7) 22.0 ± 28.2 63.6 ± 40.1
44 (80.0) 40 (72.7) 30 (54.5) 7 (12.7) 40 (72.7) 10 (18.2) 5 (9.1) 11 (20.0) 9 (16.4) 25 (45.5) 8 (14.5) 0 (0) 7.8 ± 13.1 78.2 ± 71.8
1.000 0.061 0.022‡ 0.016‡ 0.061 0.016‡ 0.281 0.824 1.000 1.000 1.000 – 0.001‡ 0.672
0.295 (0.089, 0.983) 4.092 (1.374, 12.187)‡ 1.841 (0.765, 4.427) 3.355 (1.275, 8.827)‡ 2.068 (0.768, 5.573) 3.018 (1.235, 7.378)‡ 1.653 (0.510, 5.359) 0.681 (0.250, 1.855) 0.536 (0.179, 1.606) 1.531 (0.709, 3.307) 1.330 (0.463, 3.820) – – –
*Data presented as n (%) or mean ± standard deviation; †p obtained from independent t test or Pearson’s χ2 test; ‡significant at p < 0.05 level. aOR = adjusted odds ratio, all adjusted for gestational age in weeks; CI = confidence interval; VAP = ventilator-associated pneumonia; IVH = intraventricular hemorrhage; ROP = retinopathy of prematurity.
mechanical ventilation (aOR, 4.092; 95% CI, 1.374, 12.187), as well as ventilation over 5 days (aOR, 2.654; 95% CI, 1.127, 6.252). The incidence of NEC was low, with three cases in the CAM group and none in the non-CAM group. There were no cases of early neonatal sepsis in either group; all 28 cases with neonatal septicemia had ventilator-associated pneumonia (VAP), and none of them had primary neonatal septicemia. Neonatal septicemia and VAP were strongly related J Formos Med Assoc | 2008 • Vol 107 • No 4
to histological CAM (21 in the CAM group and 7 in the non-CAM group). The majority of organisms included Candida parapsilosis (n = 4), Acinobacter baumannii (n = 4), Klebsiella pneumoniae (n = 3), Serratia marcescens (n = 3) and Staphylococcus epidermidis (n = 3). At the corrected ages of 6, 12, 18 and 24 months, anthropometric growth of infants, including body weight, body height and head circumference, were similar in both groups (Table 4). 307
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Table 4. Growth of anthropometry* CAM (n = 64)
Non-CAM (n = 55)
p
6 mo BW BH HC
6.8 ± 1.1 64.2 ± 3.7 50.3 ± 56.3
7.1 ± 1.0 64.8 ± 3.6 42.4 ± 1.3
0.254 0.453 0.375
12 mo BW BH HC
8.7 ± 1.2 72.8 ± 3.5 44.6 ± 1.6
8.7 ± 1.0 71.2 ± 9.3 45.0 ± 1.3
0.921 0.314 0.181
18 mo BW BH HC
10.1 ± 1.4 79.6 ± 4.1 45.9 ± 1.7
9.8 ± 1.2 78.4 ± 3.2 46.2 ± 1.4
0.284 0.153 0.442
24 mo BW BH HC
11.5 ± 2.4 85.1 ± 4.1 46.9 ± 1.7
11.2 ± 1.3 84.3 ± 3.4 46.8 ± 1.1
0.444 0.401 0.940
*Data presented as mean ± standard deviation. BW = body weight; BH = body height; HC = head circumference.
Discussion In our study, there were 53.8% of placentas with CAM, similar to Dexter et al’s report (57%).12 The number of cases of CAM increased with decreasing gestational age, which was consistent with previous studies.13 Thus, placental inflammation is a common finding in preterm gestation. The etiology of preterm delivery of a fetus with CAM might be directly related to infection; however, clinical evidence of infection is rarely detected, so the diagnosis is usually made through histologic examination of the placenta. In our study, CAM was not an indication for cesarean section, but rather, acute perinatal events were. This reflects that histological CAM is a chronic or subacute inflammatory condition of the placenta. Romero et al6 have shown that a fetal inflammatory process may be followed by the spontaneous onset of preterm labor. It is also possible that inflammation impairs placental function. The rate of maternal steroid use was 51.6% in the CAM group compared to 36.4% in the non-CAM group. In the non-CAM group, there 308
were more preterm deliveries for maternal reasons or the time from arrival to delivery was insufficient to obtain a fetal steroid response. These factors possibly accounted for differences in steroid use. In this study, there was one case of clinical CAM in the histological CAM group and no cases with microbial evidence in either group. We did not have enough cases of clinical CAM to investigate the histological findings and outcome. The prevalence of PPROM was 46.9% and 10.9% (p < 0.001) in the CAM and non-CAM groups, respectively. The cases with CAM had a longer duration of ruptured membranes.14,15 This supports the concept that intra-amniotic infection is frequently caused by organisms in the lower genital tract that ascend into the uterine cavity. In addition to preterm delivery, CAM increases neonatal morbidity and mortality. Hagberg et al16 have summarized the sequelae of CAM in both term and preterm infants. We identified a higher incidence of BPD, greater use of surfactant, and more days of ventilation in the CAM group. CAM leads to a fetal inflammatory response, which is characterized by elevated cytokine levels. CAM is J Formos Med Assoc | 2008 • Vol 107 • No 4
Outcome and growth anthropometry in VLBW infants with chorioamnionitis
reported to cause accelerated but abnormal lung maturation, which results in decreased incidence of RDS, but increased BPD.17 Our study, which showed that histological CAM increased the risk of BPD (p = 0.016; aOR, 3.018), was consistent with previous studies.17,18 However, there was no significant association between CAM and RDS (p = 0.061; aOR, 2.068). Pulmonary inflammation is a key feature in the pathogenesis of BPD. This inflammatory process, induced by multiple risk factors, is characterized by the presence of inflammatory cells, cytokines and an arsenal of additional humoral mediators in the airways and pulmonary tissue. Intrauterine exposure to proinflammatory cytokines or antenatal infection may prime the fetal lung such that minimally injurious postnatal events provoke an excessive pulmonary inflammatory response that affects normal alveolization and pulmonary vascular development. This leads to difficulty in respiratory care after birth. However, in Mehta et al’s study, CAM was not a significant risk factor for BPD among neonates born at around 34 weeks of gestation.19 A few studies have demonstrated a reduction in the incidence of RDS in neonates with histological CAM.18,20 Shimoya et al identified elevated levels of interleukin-6 in cord sera of babies with CAM.21 Interleukin promotes fetal lung maturation by inducing surfactant protein-A synthesis, thereby, reducing the incidence of RDS. Our findings differ from these studies; after adjusting for gestational age, CAM had no impact on RDS. Histological CAM was strongly associated with neonatal septicemia. Most septicemic patients were delivered within 24 hours of membrane rupture, which highlighted the potential role of infection in premature delivery. In this study, there was no case of early neonatal sepsis. These findings are not consistent with those of other studies.22,23 All the neonatal septicemia in our study occurred after the age of 3 days. Most of the organisms included C. parapsilosis, A. baumanni, K. pneumoniae and S. marcescens. They were also found in sputum culture that was aspirated from an endotracheal tube; therefore, these cases had VAP too. VAP is an airway infection J Formos Med Assoc | 2008 • Vol 107 • No 4
that develops 48 hours after the patient is intubated. Because the CAM group had longer ventilation days (p = 0.001), it was reasonable that VAP occurred more frequently in this group. In our study, CAM was a risk factor for neonatal septicemia with VAP (aOR, 3.355; 95% CI, 1.374, 12.187). There were no significant differences in PDA, retinopathy of prematurity (all grades and grade > III), IVH (all grades or stratification of grades III and IV) and NEC. This was not the same as the study of Salafia et al,24 who found that early germinal matrix/IVH occurred more frequently in infants delivered with a placenta showing amniotic inflammation. In our study, the gestational age of the CAM group was significantly shorter than that of the non-CAM group. However, the IVH incidences were similar, although theoretically, IVH occurred more frequently in babies of younger gestational age. For NEC, there were only three cases in the CAM group and none in the nonCAM group, so a type 2 error must be considered. There have been no previous studies investigating the effect of CAM on anthropometric growth. Morbidity was increased among preterm infants with CAM, thus the anthropometric growth might be affected. In our study, at corrected ages of 6, 12, 18 and 24 months, the two groups of premature infants showed similar growth, including body weight, height and head girth. In conclusion, histological CAM was associated with increased risk of BPD and sepsis in VLBW premature infants. However, it was not associated with survival, PDA, IVH, NEC, retinopathy of prematurity and anthropometric growth within 2 years after birth.
Acknowledgments This study was supervised by the Ethics Committee and Institutional Review Board of Shin-Kong Medical Center. We thank Miss Chang Chia-Han for manuscript preparation and computational analyses, Ms Li Yu-Ling for technical assistance, and Dr Bai Chyi-Huey for statistical analysis. This 309
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project was supported by a grant from Shin-Kong Wu Ho-Su Memorial Hospital (SKH-FJU-96-20).
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